Antidepressant medications are prescribed to millions of Americans, many of whom receive the drug for months to years. Despite increasingly sophisticated studies in animals and the development of more biochemically specific antidepressants, the therapeutic mechanism of action in man remains unknown. Comparison of biochemical effects in CSF, plasma and urine in the same patients is now feasible with new, efficient high performance liquid chromatography assays, and, when coupled with physiologic, behavioral and neuroendocrine measures, allows for clearer systems interpretations of changes. Findings of particular interest include the following: 1. Effects on norepinephrine (NE) of several antidepressants instead of on serotonin (5HT) or dopamine (DA) support a hypothesis that a prerequisite for therapeutic action is increased efficiency of the noradrenergic system associated with stabilized regulation of other systems dependent on NE. 2. Differential responses of NE to lithium but not zimelidine, a 5HT, or desipramine, a NE uptake inhibitor, occur in healthy volunteers vs. patients. This provides a new lead on the bidirectional effect of lithium. 3. Reversal of certain specific alcohol-induced memory deficits by zimelidine is an exciting finding consistent with our previous finding that it stimulates the peptide, vasopressin, which is implicated in memory function. 4. Chinese vs. caucasian differences in dose requirements is explained by differences in drug metabolism although the previously hypothesized responsible enzymatic step ahs been ruled out. Ours is the first data challenging a generally held assumption about relevant pharmacogenetics. 5. Clorgyline, a specific monoamine oxidase Type A inhibitor, has now been found to show potent antidepressant effects in unipolar as well as bipolar patients who have failed to respond to other treatments, including ECT.